Dopamine Receptor D4 as a Therapeutic Target for Alzheimer’s Disease Drug Discovery

Overview

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of neuritic plaques and neurofibrillary tangles, leading to cognitive decline and neuronal death. Current therapeutic approaches, including recently FDA-approved drugs Lecanemab and Donanemab, target the removal of amyloid-β deposits and are indicated for patients with mild AD. While these drugs can slow progression in early or mild stages, they remain ineffective in late-stage AD, as plaque burden is higher and amyloid-β clearance becomes limited. Given these limitations, we sought to identify alternative gene pathways that may contribute to AD development. We performed differential expression analysis using the linear models for microarray data (LIMMA) method to identify genes associated with severe cases of AD. Our investigation identified Dopamine Receptor D4 (DRD4) as a gene consistently down-regulated in severe stages of AD. The pronounced downregulation of DRD4 in severe AD suggests that targeting this pathway may serve as a strategy to prevent amyloid plaque formation during the late stages of disease and prevent late-stage neurodegenerative processes. Subsequently, we aimed to identify molecular agonist compounds capable of upregulating DRD4 expression and enhancing its signaling pathways, intending to improve neuronal function and potentially mitigate the neurodegenerative processes associated with AD. We created and trained a GPT-2-based LLM on a dataset consisting of drug sequences and their corresponding target gene and protein sequences using supervised and reinforcement learning. The model was used to create candidate molecules, which were then optimized and validated with molecular docking and ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) analysis through Schroedinger Maestro. Our results, showing strong absorption, safety, and increased DRD4 activation, position our lead compound, a fused-ring aromatic compound methylbenzocyclobutene, as a promising late-stage AD therapeutic candidate, with in vivo validation planned as the next phase of study to explore full-body physiological effects.